Wolbachia is a genus of bacteria that infects arthropods, including insects and crusteans, and filarial worms such as Onchocerca volvulus, Wuchereria bancrofti, Brugia malayi, and Brugia timori. The bacteria reside in cytoplasmic vacuoles and are essential for development, reproduction and long-term survival of filarial worms.
Onchocerca volvulus is a causative agent of onchocerciasis, or river blindness, in humans. Manifestations of onchocerciasis result primarily from the intense inflammatory reaction to Wolbachia bacteria released into the skin and eyes upon the death of microfilaria. Onchocerciasis affects up to 37 million people worldwide and is most abundant in Africa.
Wuchereria bancrofti, Brugia malayi, and Brugia timori are causative agents of lymphatic filariasis, or elephantiasis, in humans. People suffering with lymphatic filariasis can develop hydrocele and lymphedema leading to elephantiasis. It is estimated that up to 120 million people in 83 countries worldwide are affected by lymphatic filariasis.
Two of the major constraints of treatment of filarial diseases are (i) the absence of a macrofilaricidal drug (or for onchocerciasis, one which permanently sterilizes the worm) and (ii) the risk of worms developing drug-resistance. For example, currently available treatments for onchocerciasis include ivermectin, which kills worm larvae, but has little or no activity against adult Onchocerca volvulus parasites. Thus, infected patients must be retreated with ivermectin for several years until the adult worms die naturally. The most commonly used dose interval is 12 months; however, retreatment with ivermectin may be considered at intervals as short as 3 months. In addition, there are also potential signs of resistance to ivermectin within the parasite in a few areas. Osei-Atweneboana M Y, et al. (2011) Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus. PLoS Negl Trop Dis 5(3): e998. In addition, there is a danger in treating patients co-infected with both (i) Wuchereria bancrofti, Brugia malayi, Brugia timori, and/or Onchocerca volvulus; and (ii) Loa loa with ivermectin. In such co-infected patients, ivermectin treatment can cause severe reactions, including encephalopathy, leading to coma or even death. Thus, alternative, and more effective, treatments for filarial worm diseases and, in particular, onchocerciasis and lymphatic filariasis are needed.
Antibiotics, such as doxycycline, minocycline, and rifampicin, have been demonstrated to be effective against Wolbachia. Taylor et al., (2005) Lancet. 365(9477):2116-2121 and Townson S, et al., (2006) Filaria J. 5:4. However, it has been reported that other classes of antibiotics, such as penicillins, aminoglycosides, and macrolides are ineffective at depleting Wolbachia from filariae. Hoerauf A, et al. (1999) Journal of Clinical Investigation 103(1):11-18 and Hoerauf A, et al. (2000) Trop Med Int Health 5(4):275-279.
Existing anti-Wolbachia drugs are non-optimal; they require a relatively long course of treatment (˜4 weeks) and often exclude certain subjects, including pregnant women and children under the age of 9 (e.g., with tetracyclines). Thus, there exists a need for better anti-Wolbachia treatments, such as those providing a shorter treatment regimen (e.g., 7 days or less) and usable in currently restricted populations (Taylor et al. Parasitology, 141(1):119-27).